Genetic Mutation Accelerates CTE Pathology

Phosphorylated tau pS422 immunoreactive profiles in the cortex of P301Smice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu.

Phosphorylated tau pS422 immunoreactive profiles (dark brown) in the cortex of P301S mice after repetitive mild TBI. Image courtesy of Dr. Leyan Xu, Department of Pathology, Johns Hopkins University.

Over the course of a football game or a boxing match, athletes may experience a series of mild concussions. Some of these athletes develop a condition known as chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by the build-up of abnormal tau protein that eventually leads to dementia. But not every athlete develops CTE after repetitive mild traumatic brain injury, and scientists think genetic factors are involved.

In a recent study, researchers at the Johns Hopkins University School of Medicine found that the density of abnormal tau protein increased exponentially in mice that had a genetic mutation thought to cause neurodegenerative diseases. Their findings contrast with previous studies of mice without genetic mutation, where abnormal tau protein build-up did not occur. This evidence leads the scientists to infer that genetic factors play a role in the onset of CTE.

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Munich Researchers Use WormLab to Study Blast Effects on C. elegans

 

Explosions can tear apart buildings, send shrapnel flying, and hurtle humans into the air. But explosions also cause damage in ways that aren’t as visually apparent. Scientists say the force of a blast can cause brain damage, but questions linger about how the symptoms that emerge after a blast-induced traumatic brain injury are connected to the initial trauma.

In their quest to learn more about how symptoms emerge after a traumatic blast, researchers at the Ludwig-Maximilians University of Munich, in Munich, Germany have developed an animal model of blast-related mild traumatic brain injury (br-mTBI) using C. elegans – a popular model organism alternative to vertebrate animals.

In their study, published in Frontiers in Behavioral Neuroscience, the research team used WormLab to analyze thousands of worms. They found that shockwaves either slowed the worms’ movements or rendered them paralyzed. Symptoms played out in a dose-dependent manner, meaning that worms exposed to a higher number of shockwaves displayed a higher severity of symptoms.

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Delayed loss of neurons occurs in mice with mild TBI and anxiety

Almeida-Suhett et al saw delayed loss of GABAergic interneurons in the BLA within the first week after mild CCI. (Representative photomicrographs of GAD-67 immunohistochemically stained GABAergic interneurons in the BLA of sham (left), 1-day CCI (middle), and 7-day CCI (right) animals. Total magnification is 630x; scale bar, 50 µm.)

Almeida-Suhett et al saw delayed loss of GABAergic interneurons in the BLA within the first week after mild CCI. (Representative photomicrographs of GAD-67 immunohistochemically stained GABAergic interneurons in the BLA of sham (left), 1-day CCI (middle), and 7-day CCI (right) animals. Total magnification is 630x; scale bar, 50 µm.)

Soldiers, athletes, and other individuals who suffer a traumatic brain injury often develop anxiety disorders, but scientists aren’t sure why. Some speculate that fear about future health or the stress of the trauma itself contributes to elevated anxiety, while others suspect changes happening inside the brain as a result of the injury are to blame.

Researchers at Maria Braga’s lab at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, recently found direct evidence that physical changes happen in the brain after TBI that coincide with increased anxiety levels.

She and her team studied a rat model of mild TBI, focusing on the basolateral amygdala (BLA) – a brain region often damaged by TBI, which has also been associated with increased fear and anxiety in instances of hyperactivity.

To find out what happens in the BLA that might be causing anxiety after a mild TBI, the researchers analyzed changes in synaptic activity in this region. Using Stereo Investigator with the optical fractionator probe to perform a stereological quantification of Nissl-stained and GAD-67 immunostained brain cells, they found that many of the inhibitory neurons – the cells that quiet activity – were lost seven days after injury. Whole cell recordings from principal neurons confirmed that the inhibitory cells’ synaptic transmissions were impaired during this period, resulting in increased excitability and “open field tests” showed elevated anxiety levels in post-injury rats at the exact same time point. Continue reading “Delayed loss of neurons occurs in mice with mild TBI and anxiety” »

Scientists Use Stereo Investigator in Spinal Cord Injury Study

Stereo Investigator Graphic

After an initial spinal cord injury, a cascading series of secondary events continues to do damage to the nervous system. One particularly damaging event is the death of oligodendrocytes—neuroglial cells that help protect and support the central nervous system. Scientists are learning more about the mechanisms involved in this process in the hope that their research may lead to the development of new therapeutic treatments for stopping some of the secondary damage before it occurs.

Researchers at the Miami Project to Cure Paralysis previously found that astrocytes play a role in oligodendrocyte death after spinal cord injury, but they weren’t quite sure how. Their new study identifies a culprit – an enzyme called NADPH oxidase. According to their paper, published in PLOS One, astrocytes activate NADPH oxidase within oligodendrocytes after an injury, triggering a toxic effect in the tiny neural cells.

In their study, the researchers set out to see what would happen if they could prevent post-trauma NADPH oxidase activation. Their results proved promising, with both in vitro and in vivo experiments resulting in lower oligodendrocyte death.

Continue reading “Scientists Use Stereo Investigator in Spinal Cord Injury Study” »

Florida Researchers Study Traumatic Brain Injury With Stereo Investigator

journal.pone.0053376.g003

Figure 3 from “Hippocampal CA3 cell loss and downregulation of cell proliferation.”

If a head gets hit hard enough, the trauma occurs instantly. Neurons die, the brain swells as microglia cells rush to the damaged area, and the protective armor known as the blood brain barrier might even rupture. But it doesn’t end there. Long term effects include cognitive impairment, loss of sensory processing, and susceptibility to neurodegenerative diseases like Alzheimer’s.

Researchers at the University of South Florida say patients suffering from chronic Traumatic Brain Injury (TBI) experience a “cascade of events” marked by long-term neuroinflammation, cell loss, and impaired cell proliferation that may manifest over time.

“While TBI is generally considered an acute injury, a chronic secondary cell death perturbation (i.e., neuroinflammation) and a diminished endogenous repair mechanism (i.e., cell proliferation) accompany the disease pathology over long-term,” the authors say in their paper published this month in PLOS ONE.

The scientists used unbiased stereology to analyze activated microglia cells, cell proliferation, and differentiation into immature neurons in several regions of the brains of rats which had experienced TBI eight weeks prior.

They used Stereo Investigator with the Cavalieri estimator probe and the optical fractionator probe to estimate the quantity and volume of stained cells in the cortex, striatum, thalamus, fornix, cerebral peduncle, and corpus callosum, as well as the subgranular zone and the subventricular zone in both hemispheres of the brain.

Eight weeks after the TBI occurred, the researchers found an increased level of active microglia cells at the direct site of the TBI as well as surrounding regions. They also report a decrease in hippocampal neurons, and low levels of cell proliferation in the neurogenic niches.

“Our overarching theme advances the concept that a massive neuroinflammation after TBI represents a second wave of cell death that impairs the proliferative capacity of cells, and impedes the regenerative capacity of neurogenesis in chronic TBI,” the authors say in their paper.

They go on to suggest a “multi-pronged treatment targeting inflammatory and cell proliferative pathways” may help alleviate the pathological effects of chronic TBI.

Read the full paper “Long-Term Up-regulation of Inflammation and Suppression of Cell Proliferation in the Brain of Adult Rats Exposed to Traumatic Brain Injury Using the Controlled Cortical Impact Model” on PLOS ONE.

{Acosta S.A., Tajiri N., Shinozuka K., Ishikawa H., Grimmig B., et al. (2013). Long-Term Up-regulation of Inflammation and Suppression of Cell Proliferation in the Brain of Adult Rats Exposed to Traumatic Brain Injury Using the Controlled Cortical Impact Model. PLoS ONE 8(1): e53376. doi:10.1371/journal.pone.0053376}

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